Pharmaceutical compositions and methods for producing coronary dilation with 4 - aryl-1 4 - dihydropyridine derivatives

ABSTRACT

4-PHENYL-, 1,4-DIHYDROPYRIDINES OF THE FORMULA:   2,6-DI(R-),3,5-DI(R&#39;&#39;-OOC-),4-(R&#34;-PHENYL)-1,4-DIHYDRO   PYRIDINE   WHEREIN R IS HYDROGEN OR ALKYL OF 1 TO 3 CARBON ATOMS, R&#39;&#39; IS ALKYL OF 1 TO 4 CARBON ATOMS, AND R&#34; IS HYDROGEN, HALOGEN, OR 1 OR 2 LOWER ALKYL, LOWER ALKOXY, NITRO, LOWER ACYLAMINO, LOWER ALKYLAMINO OR AMINO MOIETIES ARE PRODUCED BY REACTING BENZALDEHYDES OR SUBSTITUTED BENZALDEHYDES WITH ACYL FATTY ACID ESTERS OF THE FORMULA R-CO-CH2-COOR&#39;&#39; WHEREIN R AND R&#39;&#39; ARE AS ABOVE DEFINED WITH AMMONA. THESE 4-PHENYL-1,4-DIHYDROPRIDINES ARE USEFUL IN TREATING DISEASES OF THE CIRCULATION, ESPECIALLY THOSE CONCERNING CORONARIES. THEY ARE PARTICULARLY USEFUL IN THE TREATMENT OF ANGINA PECTORIS.

United States Patent Int. Cl. Adlk 27/00 U.S. Cl. 424-266 51 Claims ABSTRACT OF THE DISCLOSURE 4-phenyl-1,4-dihydropyridines of the formula:

wherein R is hydrogen or alkyl of 1 to 3 carbon atoms,

R is alkyl of 1 to 4 carbon atoms, and

R" is hydrogen, halogen, or 1 or 2 lower alkyl, lower alkoxy, nitro, lower acylamino, lower alkylamino or amino moieties are produced by reacting benzaldehydes or substituted benzaldehydes with acyl fatty acid esters of the formula RCOCH COOR' wherein R and R are as above' defined with ammonia.

These 4-phenyl-l,4dihydropyridines are useful in treatting diseases of the circulation, especially those concerning coronaries. They are particularly useful in the treatment of angina pectoris.

This application is a continuation application of Ser. No. 829,099, filed May 29, 1969, and now abandoned, which in turn is a divisional application of Ser. No. 712,910, filed Mar. 14, 1968, now US. Pat. 3,485,847, granted Dec. 23, 1969.

The present invention is concerned with 4-aryl-1,4-dihydropyridines. More particularly, the present invention is concerned with 4-phenyl-1,4-dihydropyridines of the formula:

wherein R is hydrogen or alkyl of 1 to 3 carbon atoms,

R is alkyl of 1 to 4 carbon atoms, and

R" is hydrogen, halogen, or 1 or 2 lower alkyl, lower alkoxy, nitro, lower acyl amino, lower alkylamino or amino moieties. These compounds are prepared by reacting benzaldehyde or benzaldehydes substituted by halogen, l or 2 lower alkyl, lower alkoxy, nitro, lower 3,644,627 Patented Feb. 22, 1972 "ice acylamino, lower alkylamino or amino moieties with acyl fatty acid esters of the formula wherein R and R are as above defined with ammonia in the presence of an organic solvent, such as methanol or alcohol. The amino-substituted compounds are obtained by reduction of the corresponding nitro compounds.

Because of the increasing importance of therapeutic substances which can be used in the treatment of diseases of the circulation and particularly those involving coronaries of the heart, the compounds of the present invention are of particular importance. Moreover, the compounds which are presently commercially available, such as dipyramidol and oarbochromene which initially appeared to be promising, based on intravenous administration to animals, have not fulfilled their initial promise and have not always shown with certainty clinical success when used in the treatment of coronary insufliciency, particularly in the treatment of angina pectoris. As a result, nitrates are still the prime medication prescribed and the effectiveness of nitrates is based on the weight of the heart.

It has now been surprisingly discovered that the compounds of the present invention produce a marked coronary dilation of long lasting duration when administered either intravenously or per 0s. The 4-phenyl-l,4- dihydropyridines of the present invention have been found to be superior to all hitherto known commercial products in duration of effectiveness and peroral effect. The action of these compounds against disturbances of the coronary blood supply is most likely favorably influenced by a nitrite effect which presumably occurs simultaneously.

The following non-limitative examples illustrate the production of compounds according to the present invention.

EXAMPLE 1 4 (2'-nitrophenyl) -2,6-dimethyl-3 ,5-dicarbomethoxy-1,4- dihydropyridine 45 g. Z-nitrobenzaldehyde, cc. acetoacetic acid methyl ester, 75 cc. methanol and 32 cc. ammonia are heated under reflux for several hours, filtered ofr', cooled and, after suction-filtration, 75 g. of yellow crystals of M.P. 172 C. to 174 C. are obtained.

In an analogous manner there are obtained:

from 2-nitrobenzaldehyde, acetoacetic acid ethyl ester and ammonia, 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine, M.P. 122 C. to 124 C.,

from 2-nitrobenzaldehyde, acetoacetic acid, isopropyl acid and ammonia, 4-(2-nitrophenyl)-2,6-dimethyl 3,5-dicarbo-isopropoxy-1,4-dihydropyridine, M.P. 140 C. to 142 C.

EXAMPLE 2 4-(3'-nitrophenyl)-2,6-dimethyl-3,S-dicarbethoxy-1,4- dihydropyridine After boiling for 6 hours, 151 g. 3-nitrobenzaldehyde, 260 cc. acetoacetic acid ethyl ester, 250 cc. methanol and cc. ammonia, there are obtained 300 g. of yellow crystals of M.P. 161 C.

In an analogous manner there are obtained:

from 3-nitrobenzaldehyde, acetoacetic acid methyl ester and ammonia, 4-(3'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, M.P. 206 C.- 208 C.,

from 3-nitrobenzaldehyde, acetoacetic acid isopropyl ester and ammonia, 4-(3'-nitropheny1)-2,6-dimethyl- 3,5 dicarbo isopropoxy-1,4-dihydropyridine, M.P. 123C,

from 3 nitro 6 chlorobenzaldehyde, acetoacetic acid ester and ammonia, 4-(3'-nitro-4'-chlorophenyl)-2,6- dimethyl 3,5-dicarbethoxy-1,4-dihydropyridine, M.P. 133 C.,

from 3 nitro 6 chlorobenzaldehyde, acetoacetic acid methyl ester and ammonia, 4-(3-nitro-6'-chlorophenyl) 2,6 dimethyl 3,S-dicarbomethoxy-1,4-dihydropyridine, M.P. 190 C.192 C.,

from 3 nitro 6 chlorobenzaldehyde, acetoacetic acid methyl ester and ammonia, 4-(3'-nitro-6'-chlorophenyl) 2,6 dimethyl 3,5 dicarbethoXy-1,4-di hydropyridine, M.P. 202 C.-205 C.

EXAMPLE 3 4-(4'-nitrophenyl)-2,6-dimethyl-3,S-dicarbethoxy-1,4- dihydropyridine 151 g. 4-nitrobenzaldehyde, 300 cc. methanol, 260 cc. acetoacetic acid ethyl ester and 110 cc. ammonia are heated under reflux for hours and, after cooling and suction-filtration, there are obtained 375 g. of yellow crystals which melt at 132 C.-134 C. after recrystallization from methanol.

In an analogous manner there are obtained:

from 4-nitrobenzaldehyde, acetoacetic acid methyl ester and ammonia, 4-(4'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy 1,4 dihydropyridine, M.P. 196 C. 197 C.,

from 4-nitrobenzaldehyde, acetoacetic acid isopropyl ester and ammonia, 4-(4-nitropheny1)-2,6-dimethyl-3,5-dicarbo-isopropoxy-1,4-dihydropyridine, M.P. 152 C.,

from 4-nitrobenzaldehyde, acetoacetic acid tert.-butyl ester and ammonia, 4-(4-nitrophenyl)-2,6-dimethyl-3,5- dicarbo-tert.-butoxy-1,4-dihydropyridine, M.P. 215 C.

EXAMPLE 4 4- (4'-aminophenyl)-2,6-dimethyl-3,S-dicarboisopropoxy-1,4-dihydropyridine 120 g. 4-(4'-nitropheny1)-2,6-dimethyl-3,S-dicarboisopropoxy-l,4-dihydropyridine are kept in 500 cc. isopropa- 1101 in the presence of g. Raney nickel under hydrogen (pressure autoclave, 70 C.) and, When the hydrogen absorption is completed (1 /2 to 2 hours), the product is filtered ofl? with suction. After concentration and cooling, pale yellow crystals of M.P. 184 C. are obtained.

In an analogous manner there are obtained from the corresponding ni-tro compound by reduction:

4 (4' aminophenyl)-2,6-dimethyl-3,S-dicarbomethoxy- 1,4-dihydropyridine, M.P. 198 C. (HCl-salt, M.P. 228 C.),

4 (4' aminophenyl) 2,6-dimethyl-3,S-dicarbethoxy- 1,4-dihydropyridine, M.P. 148 C.

4 (4' aminophenyl) 2,6-dimethyl-3,S-dicarbo-tert.

'butoxy-1,4-dihydropyridine, M.P. 191 C.

4 (3' aminophenyl) 2,6-climethyl-3,S-dicarbomethoxy- 1,4-dihydropyridine, M.P. 214 C. to 216 C.

4 (3' aminophenyl) 2.,6-dimethyl-3,S-dicarbethoxy- 1,4-dihydropyridine, M.P. 151 C.-153 C.

4 (3 aminophenyl) 2,6 dimethyl-3,5-dicarbo-isopropoxy-1,4-dihydropyridine, M.P. 250 C.

4 (2 aminophenyl) 2,6-dimethy1-3,S-dicarbomethoxy-1,4-dihydropyridine, M.P. 170 C.

4 (2' aminophenyl) 2,6-dimethyl-3,S-dicarbethoxy- 1,4-dihydropyridine, M.P. 149 C.-151 C.

4 (3' amino 4 chlorophenyl)-2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine, M.P. 215 C. (HCl salt).

4 (3 amino 6' chlorophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, M.P. 209 C. to 210 C.

4 (3' amino 6' chlorophenyl)-2,6-dimethyl-3,5-dicarbethoxy-l,4-dihydropyridine, M.P. 166 C. to 168 C. (HCl salt M.P. 242 C. to 244 C.).

EXAMPLE 5 4- (4'-dimethylaminophenyl -2,6-dimethyl-3,5- 4 dicarbomethoxy-1,4-dihydropyridine from p-dimethylamino-benzaldehyde, acetoacetic acid ethyl ester and ammonia, 4-(4-dimethylaminophenyl)- 2,6 dimethyl 3,5 dicarbethoxy-1,4-dihydropyridine, M.P. 159 C.;

from p-dimethylarnino-benzaldehyde, acetoacetic acid isopropyl ester and ammonia, 4-(4-dimethylaminophenyl) 2,6 dimethyl-3,5-dicarboisopropoxy-1,4-dihydropyridine, M.P. 164 C.;

from p-dimethylamino-benzaldehyde, acetoacetic acidsecwbutyl ester and ammonia, 4-(4'-dimethylaminophenyl) 2,6 dimethyl-3,5-dicarbo-sec.-butoxy-1,4-dihydropyridine, M.P. C.;

from p-dimethylamino-benzaldehyde, acetoacetic acid ethyl ester and ammonia, 4-(4'-dimethylaminophenyl)- 2,6 dimethyl 3,5 dicarbo-isobutoxy-l,4-dihydropyridine, M.P. 104 C.-106 C.;

from diethylamino-benzaldehyde, acetoacetic acid ethyl ester and ammonia, 4-(4'-diethylaminophenyl-2,6-dimethyl 3,5 dicarbethoxy 1,4-dihydropyridine, M.P. 159 C.;

from diethylamino-benzaldehyde, acetoacetic acid isopropyl ester and ammonia, 4-(4'-diethylaminophenyl)- 2,6 dimethyl 3,5 dicarbo-isopropoxy-1,4-dihydropyridine, M.P. 192 C.;

from m-nitro-p-dimethylamino-benzaldehyde, acetoacetic acid methyl ester and ammonia, 4-(3'-nitro-4'-dimethylaminophenyl) 2,6 dimethyl 3,5-dicarbomethoxy- 1,4-dihydropyridine, M.P. 214 C. to 216 C. vs

EXAMPLE 6 4-(2,4'-dinitrophenyl)-2,6-dimethyl-3,5

dicarbomethoxy-l ,4-dihydropyridine After heating for several hours 9 g. 2,4-dinitrobenzaldehyde, 12 cc. acetoacetic acid methyl ester and 15 cc. ammonia, there are obtained pale brown crystals 'of M.P. 202 C. to 205 C. i I

In an analogous manner there was obtained:

from 2,4-dinitrobenzaldehyde, acetoacetic acid ethyl ester and ammonia, 4-(2',4-dinitropheny1)-2,6-dimethyl-3,5, dicarbethoxy-1,4-dihydropyridine of M.P. 174 C. to 176 C. Pharmacology.-The following pharmacological data represents specific test results of 4-(2'-nitrophenyl)-2,6- dimethyl 3,5 dicarbomethoxy-l,4-dihydropyridine (II) produced according to the process described in Example 1 or 4 (4'-aminophenyl)-2,6-dimethy1-3,S-dicarbethoxy- 1,4-dihydropyridine (I) produced according to the process of Example 4. Other specific compounds of the present invention which were tested gave essentially the same results and these two compounds are, therefore, used as illustrative of the various species specifically disclosed in the generic invention as a Whole.

When compound I was administered per os to mice, the toxicity was 500 to 1000 mg./ kg. of animal weight. When compound I was administered intravenously, the LD in mice was mg./kg. The phenomenon of poisoning is unspecific. Death occurs after dyspnoea in anoxaemic spasms. In phandorom-narcosis on dogs, an increase of oxygen saturation occurs after application of a coronary catheter, when administering intravenously 0.5 mg./kg. there is a temporary increase, after 1' mg./kg. a marked to-strong increase of the oxygen, saturation in the coronary sinus up to 45% with a return to the initial value after one hour.

jQornpound I was also shown to be etfective after per os administration. Thus, in one case, after administering 20 mg./kg..of compound I, a strong" increase in blood pressure occurred which exhibited a duration of more than 4 hours.

' By means of an electromagnetic flow-test measurement at the coronary vessels dog in phanodorm narcosis), an increaseof thecoronary-blood supply up to 89% can be ascertained after administering 1 mg./kg. [i.v.]. The duration of the effect amounts up.,to-.15 minutes.

On mice compound II has LD of 375 mg./kg. per os (solvent: polyglycol) and 202 mg./ kg. per os (solvent: lutrol): It is approximately 26 rug/kg. when administered intravenously. H

" V BLOOD PRESSURE- (RATS) 0.1-2'5 mg./kg.j- (i.v.), a silght decrease during injection.

CORONARY EFFECT ON DOGS Rate of flow I 'Narcosis urethane-chloralose- With 0.005 mgl/kg. (i.v.), increase by 40%; Return to the level at the beginning of the experiments after- 1 0,minutes. 1, With 0 .01 mg ./kg. (i.v.) increase by 60%; Return to the level at the beginning of the experiments after 20 minutes. With 0.02 mg./kg. (i.v.) increase by 70%; Return. to the level at the beginning of the experiments after 30 minutes. 1 With rug/kg. (per os) still 30% above. The volume per minute increases by 55%. The blood pressure decreased in these tests by 20-60 mm. Hg.

increase by 60%; after '8 hours v M Qxygen saturation With 0.005 mg./kg; (i.v.) in 6 tests: a slight to strong increase';

Return-to the level at the beginning of the experiments I "after 30-60-minutes.

Oxygen pressure Narcosis: urethane'-cl 1loralose 0.5 mg./kg. (per os). marked increase. Return to the level at the beginning of the experiments after about 7 hours (2 tests). 10 mg./kg. (per 0s) (1 test): marked increase; Return to the level at the beginning of the experiments after 9 hours. K i 50 mg./kg. (per as) :marked increase, after 8 hours still above.

Blood pressure "-Na'rcosis: phanodorm With- 0.005; 0.01; 0.02-and 0.05 mg./kg. (i.v.): marked decrease of varying duration.

With 0.1 mg./kg. (i.v.): continuous strong decrease.

With 0.5 and 1 mg./kg. (i.v.): very strong decrease.

Narcosis: urethane-chloralose- 0.005; 0.01 and 0.02 mg./kg. (i.v.): slight decrease;

0.5 mg./ kg. (per os) strong decrease.

10 mg./kg. (per 0s): 1 test a marked, 1 test a strong decrease.

50 mg./kg. (per os) continuous strong decrease.

Frequency Narcosis: phanodorm-Varying slight effect (i.v. application).

Narcosis: urethane-chloralose 0.5 mg./kg. (per os): strong varying elfect, 10 mg./kg. (per os): strong increase, 50 mg./ kg. (per os): strong increase.

The oxygen consumption is decreased, after administering the substance with 1 mg./kg. (per os) by about 20%, with 20 'y/ kg. (i.v.) by about 50%. Simultaneously with the strongly increased coronary blood supply, a blood pressure decrease takes place which results in relieving the heart. The consequence of such a peripheral decrease in resistance is a measurable decrease in the Consumption of oxygen. 'In this respect, the compound is similar to the nitrites which are known to be very effective in clinical practice and which also bring about a determinable decrease in oxygen consumption.

The pharmacological point of attack for compound I and II is probably the smooth musculature of the vessels as such; an effect on the central or vegetative-central nervous structure could not be ascertained.

Coronary activity Compound of on dogs Example 1:

4-(2'-nitrophenyl) -2, fixlirnethyl-ii, 5-

dicarbomethoxy-l, 4-dihydropyridine.

4- (2-nitrophenyl) -2, 6-dimethyl-3, 5-

dicarbethoxy-l, 4-dihydropyridine.

4-(2 -nitrophe'nyl) -2, 6-dimethyl-3, 5-

E dicazrbo-isoproposy-l, 4-dihydropyridine.

xamp e 4-(3-nitrophenyl) -2, 6-dimethyl-3, 5-

dicarbethoxy-l, 4-dihydropyridine.

4-(3-nitropheny1)-2, 6-dimethy1-3, 5-

dicarbomethoxy-l, 4-dihydropyridine.

D dicadrbo-isopropoxy-l, 4dihydropy'ridine.

'xamp e 4-(4-nitrophenyl) -2, 6-din1ethy1-3, 5-

dicarbethoxy-l, edibydropyridine.

4-(4-nitrophenyl) -2, 6-dimethy1-3, 5-

E dliczgbo-isoporpoxy-l, 4-dihydropyridine.

xamp e 4-(4-aminophenyl) -2, 6-dimethy1-3, 5- dicarbethox y-l, 4-dihydropyridine.

4- t' -aminophenyl) -2, 6-dimethyl-3, 5- d1carb0-tert.-butoxy-l, 4-dihyd1'opyridine.

4-(3-amino6-chlorophenyl) -2, 6-

dimethyl-3, 5-diearbomethoxy-1, 4- dihydropyridine.

E a gilgdropy'ridine.

4-(4-din1ethylaminophenyl) -2, 6dimethyl- 3, E-dicarboisopropoxy-l, 4- dihydropyridine.

4- (4-diethy1aminophenyl) -2, G-(iimethyl- 3, B-dicarbethoxy-l, t-dihydropyridine.

Example 6:

4-(2, 4-dinitrophenyl) -2, 6- dimethyl-3, 5-diearbethoxy-1, 4 dihydropyridine.

0.005'002 mg./kg.,

i.v.; 0.6-1.0 mg ./kg.,

p.o. 0.01 mg./kg., i.v.

0.01 mg./kg., i.v.

0.005 mg./kg., i.v.

0.05 mg./kg., i.v.

0.005 mg./kg., i.v.

2 mg./kg., i.v.

0.2 mg./kg., i.v.

1 mg./kg., i.v.

5 rug/kg, i.v.

0.5 mg./kg., i.v.

1 mg./kg., i.v.

2 mg./kg., i.v.

5 mg./kg., i.v.

0.5 mg./kg., i.v.

The coronary-active compounds can be applied intravenously, orally, intramuscularly, but also in form of suppositories. The ampoules, capsules, sugar-coated pills,

tablets, suppositories and the like, which are contemplated for application, generally contain approximately the following quantities; these quantities are listed below for ampoules and capsules by way of example for some compounds:

Mg .lpaticnt Compound of- Ampoules Capsules Example 1:

4-(2-nitrophenyl) -2, 6-dimethyl-3,

dicarbomethoxy-l, 4-dihydropyridine- 0. 2 2. 5 4-(2-nitrophenyl) -2, 6-dimethyl-3, 5-

dicarbethoxy-l, a-dihydropyridine 0. 2 2. 5 4-(2-nitrophenyl) -2, fidimethyl-H, 5-

dicarboisopropoxy-l, 4-dlhydropyridine. 0. 2 2. 5 Example 2:

4-(3-nitrophenyl) -2, 6-dimethyl-3, 5-

diearbethoxy-l, 4-dihydropyridine 0. 2 2. 5 4(3-nitropheny1)-2, 6-dimethyl-3, 5-

dicarbometh oxy-l, Mihydropyridine 1 5 4-(3'-nitrophenyl) -2, fi-dimethyl-Ii, 5-

dicarboisopropoxy-l, 4-dihydropyridine- 0. 2 2. 5 Example 3:

4-(4'-nitropheny1) -2, 6-dimethyl-3, 5-

diearbethoxy-l, 4-dihydropyridine 5 5-10 4-(4-nitrophenyl) -2, 6-dimethyl-3, 5-

dicarboisopropoxy-l, 4 dihydropyridine 2. 5 5-10 Example 4:

Hi -aminopheny1) -2, 6-dimethyl'3, 5-

dicarb ethoxy-l, -dihydropyridine 5-15 25 4-(4J-aminophenyl) -2, 6-dimethyl-3, 5-

dicarbo-tert.-butoxy-l, Miltydropyridine- 25 4-(3-amino-6-chlorophenyl) -2, G-dimethyl- 3, fi-dicarbornethoxy-l, 4-dihydropyridine 2. 5-10 25 4-(3-amino-6-ehlorophenyl) -2, 6-dimethyl 3, 5-dicarbethoxy-l, 4-dihy dropyridine 5-l5 25 Example 5:

4-(4-dimethylaminophenyl) -2, 6-dimethyl- 3, 5-dicarboisopropoxy-1, i-dlhydropyridine 10-20 50 4-(4-diethylaminophenyl) -2, fi-dimethyl- 3, 5-dicarbethoxy-1, 4-dihydropyrldlne.-. 25 Example 6: 4-(2, 4-dinitrophenyl) -2, 6-

dimethyl-3, fi-dicarbethoxy-l, t-dihydropyridine 2. 5-10 25 For the application in human medicine in the treatment of angina pectoris 1 to 2 ampoules are to be used per day; when the compound is administered in capsules, sugarcoated pills or tablets, 3 doses should be applied per day. The aforesaid quantities refer to persons having a body weight of about 70 kg. The application of suppositories can be varied correspondingly. Nevertheless, it may be required to apply larger or lesser quantities in dependence on the body weight, the mode of application, but also on the reaction of the individual patient to the medicament and the kind of formulation thereof as well as the date and interval of administration. Thus, it may be quite sufiicient in some cases to administer less than the abovesaid minimum dosage, whereas the upper limit has to be exceeded in other cases. If larger doses are administered, it may be expedient to distribute same in several single doses during a day.

The coronary-active compounds being obvious from the disclosure and the examples, respectively, can be applied both for the treatment of an angina pectoris attack and for the prophylactic treatment of angina pectoris.

What is claimed is:

1. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of a 4-phenyl-1,4-dihydropyridine of the formula:

wherein: v R is hydrogen or alkyl of l to 3 carbon atoms, R is alkyl of 1 to 4 carbon atoms, and

R" is hydrogen, 2,4-dinitro, dilower alkylamino, amino, 3-amino-4-chloro, 3-amino-6-chloro, 3-nitro-4-dilower alkylamino, S-nitrol-chloro or 3-nitro-6-chloro,

or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable, nontoxic inert carrier.

2. A pharmaceutical composition according to claim 1 wherein R" is 2,4-dinitro.

3. A pharmaceutical composition according to claim 1 wherein R" is dilower alkylamino.

4. A pharmaceutical composition according to claim 1 wherein R" is amino.

5. A pharmaceutical composition according to claim 1 wherein R" is 3-amino-4-chloro or 3-amino-6-chloro.

6. A composition according to claim 4 wherein the therapeutically effective amount is from 0.2 to 50 mg.

7. A composition according to claim 6 comprising a unit dosage.

8. A method of preventing and treating coronary insufiiciency and angina pectoris which comprises administering to a human or animal a therapeutically effective amount of a 4-phenyl-1,4-dihydropyridine of the formula:

H 11 0001 I COOR wherein or a pharmaceutically acceptable non-toxic salt thereof.

9. A method of preventing and treating coronary insufficiency and angina pectoris according to claim 8, wherein R" is 2,4-dinitro.

10. A method of preventing and treating coronary insufiiciency and angina pectoris according to claim 8, wherein R" is dilower alkylamino,

11. A method of preventing and treating coronary insufficiency and angina pectoris according to claim 8, wherein R" is amino.

12. A method of preventing and treating coronary insufficiency and angina pectoris according to claim 8, wherein R" is 3-amino-4-chloro or 3-amino-6-chloro.

13. A method of preventing and treating coronary insufficiency and angina pectoris according to claim 8, wherein the therapeutically effective amount is from 0.2 to 50 mg. per day. 1

14. A method of preventing and treating coronary insufficiency and angina pectoris according to claim 8, wherein the administration is oral.

15. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically efiective amount of 4-(2'-nitrophenyl)-2,6-dirnethyl-3,S-dicarbomethoxy-1,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

16. A pharmaceutical composition according to claim 15 in unit dosage form.

17. A method of preventing and treating coronary insuificiency and angina pectoris which comprises administering to a human or animal a therapeutically elfective amount of 4 (2 nitrophenyl)-2,6-din1ethyl-3,5-dicarbomethoxy-l,4-dihydropyridine or .a pharmaceutically ac,- ceptable nontoxic salt thereof.

., 18. A pharmaceutical composition useful for producing coronary-dilation comprising a therapeutically effective amount of 4 (2. nitrophenyl) 2,6 dimethyl-3,5-dicarbethoxy-1,4dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

19. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically efifective amount of 4-(2'-nitrophenyl)-2,6-dimethy1 3,5 dicarbo isopropoxy-1,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

20. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(3'-nitrophenyl)-2,6-dimethyl-3,S-dicarbethoxy-l,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

21. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4(3-nitrophenyl) 2,6 dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier. 1

22. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(3'-nitrophenyl)-2,6-dimethyl 3,5 dicarboisopropoxy-1,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

23. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3'- nitro-4'-chlorophenyl) 2,6 dimethyl-3,5-dicarbethoxy- 1,4-dihydropyridine.

24. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3- nitro-6-chlorophenyl)-2,6-dimethyl-3,5 dicarbomethoxy- 1,4-dihydropyridine.

25. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3- nitro-6'-chlorophenyl)-2,6-dimethyl 3,5 dicarbethoxy- 1,4-dihydropyridine.

26. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(4'-nitrophenyl)-2,6-dimethyl-3,S-dicarbethoxy-l,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

27. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(4'-nitrophenyl) -2,6-dimethyl 3,5 dicarbomethoxy-l,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

28. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(4'-nitrophenyl)-2,6-dimethyl 3,5 dicarboisopropoxy-1,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

29. A pharmaceutical composition useful for producing coronary dilation comprising a therapeutically effective amount of 4-(4-nitrophenyl)-2,6-dimethyl 3,5 dicarbotert.-butoxy-l,4-dihydropyridine or a pharmaceutically acceptable non-toxic salt thereof, in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.

30. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4'- aminophenyl) -2,6-dimethyl 3,5 dicarbo-isopropoxy-1,4- dihydropyridine.

31. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4'.- aminophenyl)-2, 6-dimethyl 3,5 dicarbomethoxy-l,4dihydropyridine.

32. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4 dihydropyridine is 4-(4'- ammophenyl)-2,6-dimethyl 3,5 dicarbethoxy-1,4-dihydropyridine.

33. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4'- aminophenyl)-2,6-dimethyl 3,5 dicarbo tert. butoxy- 1,4-dihydropyridine.

34. The pharmaceutical composition according to claim 1 wherein the 4-phenyll',4-dihydropyridine is 4-(3'- aminophenyl)-2,6-dimethyl 3,5 dicarbomethoxy-1,4-dihydropyridine.

35. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3- aminophenyl)-2,6-dimethyl 3,5 dicarbethoxy-1,4-dihydropyridine.

36. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3'- aminophenyl)-2,6-dimethyl 3,5 dicarbo-isopropoxy-1,4- dihydropyridine.

37. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(2'- aminophenyl)-2,6-dimethyl 3,5 dicarbomethoxy-1,4-dihydropyridine.

38. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(2'- aminophenyl) 2,6 dimethyl-3,5-dicarbethoxy-l,4dihydropyridine.

39. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3'- amino-4-chlorophenyl)-2,6-dimethyl 3,5 dicarbethoxy- 1,4-dihydropyridine.

40. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3'- amino-6'-chlorophenyl) 2,6 dimethyl 3,5 dicarbomethoxy-l,4-dihydropyridine.

41. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(3- amino-6'-chlorophenyl)-2,6-dimethyl 3,5 dicarbethoxy- 1,4-dihydropyridine.

42. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4(4'- dimethylaminophenyl) 2,6 dimethyl 3,5 dicarbomethoxy-1,4-dihydropyridine.

43. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4- dimethylaminophenyl) 2,6 dimethyl-3,S-dicarbethoxy- 1,4-dihydropyridine.

44. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4'- dimethylaminophenyl) 2,6 dimethyl 3,5 dicarboisopropoxy-l,4-dihydropyridine.

45. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4'- dimethylaminophenyl) 2,6 dimethyl 3,5 dicarbo-sec.- butoxy-1,4dihydropyridine.

46. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-l,4-dihydropyridine is 4-(4'- dimethylaminophenyl) 2,6 dimethyl 3,5 dicarbo-isobutoxy-1,4-dihydropyridine.

47. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4- diethylaminophenyl) 2,6 dimethyl 3,5 dicarbethoxy- 1,4dihydropyridine.

48. The pharmaceutical composition according to claim 1 wherein the 4-phenyl-1,4-dihydropyridine is 4-(4- "'3i i 5 V KQI'Iiet'arii et al., Chern. Abstracts, vol. 65, par. 2009 2- 4 2 ni'trophenyl) 2,5 4 dimethyl 3,5 dicarbethoxy-1,4-dihydropyridine.

I References Cited j Ch em. Abstracts, v61. 64, par. 713-714, 1966.

20094, December 1966.

Treibs. et aL, Chern. Abstracts, vol. 57, par. 2031-2033,

Karnal et al., Chem. Abstracts, vol. 61, par. 5605, 1964.

SIANLEY J. FRIEDMAN, Primary Exarriiner 

